Solid compositions suitable for oral administration containing non-hygroscopic salts of L-carnitine and the alkanoyl L-carnitines with taurine chloride and glycine chloride

ABSTRACT

Described herein are both non-hygroscopic salts of L-carnitine and alkanoyl L-carnitine with taurine chloride (2-aminoethane-sulphonic chloride) and non-hygroscopic salts of L-carnitine and alkanoyl L-carnitine with glycine chloride which lend themselves favorably to the preparation of solid compositions suitable for oral administration. Also described are solid compositions containing said salts.

This application is the US national phase of international applicationPCT/IT01/00503 filed 28 Sep. 2001, which designated the US.

The invention described herein relates to physiologically acceptablesalts of L-carnitine and alkanoyl L-carnitine, characterised in thatthey are non-hygroscopic and stable. Said salts lend themselvesfavourably to the preparation of solid compositions suitable for oraladministration. The invention also relates to pharmaceutical andalimentary or nutritional compositions containing them.

It is well known that carnitine and its alkanoyl derivatives lendthemselves to various therapeutic uses. For example, L-carnitine is usedin the cardiovascular field for the treatment of acute and chronicmyocardial ischaemia, angina pectoris, heart failure and cardiacarrhythmias.

In the nephrological field, L-carnitine is administered to uraemicpatients on regular haemodialysis treatment to combat muscular astheniaand the onset of muscle cramps.

Other therapeutic uses relate to the restoration of a normalHDL/LDL+VLDL ratio and total parenteral nutrition.

It is also well known that the salts of L-carnitine and its alkanoylderivatives known to date present the same therapeutic or nutritionalactivities as the so-called “inner salts” and can therefore be used intheir place, provided such salts are “physiologically acceptable”, thatis to say they do not present toxic or unwanted side effects.

In practice, then, the choice between an inner salt and an actual saltof L-carnitine or alkanoyl L-carnitine has depended to date exclusivelyon which compound was more easily or economically available and onconsiderations of pharmaceutical technology rather than onconsiderations of therapeutic or nutritional activity.

The purpose of the invention described herein is to provide stable,non-hygroscopic salts of L-carnitine and the lower alkanoyl L-carnitinesthat present in addition an increased therapeutic and/or nutritionalvalue compared to the corresponding inner salts.

It should therefore be clearly understood that the usefulness of thesalts according to the invention described herein consists not only intheir non-hygroscopicity and their greater stability compared to thecorresponding inner salts, but also in the fact that their anionic partcontributes to the therapeutic and/or nutritional value of the salt as awhole, such value therefore not being exclusively determined by the“carnitine” part of the salt.

The non-hygroscopicity of these salts makes them easier to process,particularly in view of the preparation of solid oral administrationforms.

As experts in pharmaceutical technology are well aware, the processingof hygroscopic products entails the use of controlled humidity chambersfor both storage and processing.

In addition, the finished product must be packaged in hermeticallysealed blister packs to avoid the disagreeable consequences of humidity.

All this implies greater storage costs for the raw materials and fortheir processing and packaging.

Among the populations of the industrialised countries there is anincreasing use of food supplements or “nutraceuticals” by sportsmen(amateurs or professionals) and also by people in a good state ofhealth.

Sportsmen use L-carnitine or food supplements containing carnitinebecause it favours the oxidation of fatty acids and makes available agreater amount of energy to skeletal muscle, thus permitting enhancedperformance and giving rise to less accumulation of lactic acid in theathletes' muscles.

People in a good state of health use these food supplements as healthfoods, i.e. for the purposes of favouring a reduction in serum levels offats and restoration of a normal ratio between the various cholesterolfractions with a view to preventing diseases related to lipid metabolismdisorders.

It has been estimated that the amount of L-carnitine and its derivativessold for non-ethical purposes is twice that sold for ethical purposes.

The US market for health foods or nutraceuticals amounts toapproximately 250 billion dollars, whereas the estimated figure for theEuropean market is around 500 billion dollars (Food Labeling News, 1994,“Nutraceuticals” Market said to be a vast one, March, Vol. 2, N° 25;King Communications Group Inc., 1993, “Nutraceuticals” Foods, Drink inGlobal Market, Food and Drink Daily, April, Vol. 3, N° 503).

A number of non-hygroscopic salts of L-carnitine or the alkanoylL-carnitines are already known.

For example, European patent 0 434 080 (Lonza) filed on Dec. 21, 1990describes the use of a non-hygroscopic salt of L-carnitine withL(+)-tartaric acid (salt already described by Múller and Strack inHoppe-Seyler's Z. Physiol. Chem., 353, 618-622, April 1972) for thepreparation of solid oral administration forms.

This salt, however, presents a number of drawbacks, such as, forinstance, the release of trimethylamine after prolonged storage, whichproduces a disagreeable odour due to the characteristic fishy smell ofthis amine.

In addition, L-(+)-tartaric acid is not capable of furnishingnon-hygroscopic salts with alkanoyl L-carnitines such as, for example,acetyl L-carnitine.

It should also be noted that the tartrate anion is not capable, alone,of increasing the therapeutic and/or nutritional value of carnitine.

U.S. Pat. No. 4,602,039 (Sigma Tau) describes the fumarates ofL-carnitine, acetyl L-carnitine and propionyl L-carnitine.

While L-carnitine fumarate is highly non-hygroscopic, resisting evenbetter than L-carnitine tartrate in a milieu with a high relativehumidity content, this property seems to diminish on increasing theweight of the alkanoyl radical.

WO98/43945 describes solid compositions suitable for oral administrationcontaining non-hygroscopic salts of L-carnitine and the alkanoylL-carnitines with 2 aminoethanesulphonic acid (taurine).

WO98/45250 describes solid compositions suitable for oral administrationcontaining L-carnitine and alkanoyl L-carnitine magnesium tartrate.

WO98/44918 describes solid compositions suitable for oral administrationcontaining alkanoyl L-carnitine magnesium citrate.

WO98/47857 describes solid compositions suitable for oral administrationcontaining L-carnitine choline tartrate or alkanoyl L-carnitine cholinetartrate.

WO98/49134 describes solid compositions suitable for oral administrationcontaining L-carnitine and alkanoyl L-carnitine magnesium fumarate.

The above-mentioned purpose of the invention described herein istherefore to form new pharmacologically acceptable non-hygroscopic,stable salts of both L-carnitine and the lower alkanoyl L-carnitines inwhich the anionic part contributes to the therapeutic and/or nutritionalvalue of the salt.

The object of the invention described herein is therefore a salt ofL-carnitine with taurine chloride (chloride salt of2-amino-ethane-sulphonic acid) of general formula (I)

wherein R is hydrogen or a straight or branched lower alkanoyl, with 2-5carbon atoms.

The salts in which R is selected from the group consisting of acetyl,propionyl, butyryl, valeryl and isovaleryl are to be preferred.

As mentioned above, international patent application WO98/43945 filed inthe name of the applicant describes solid compositions suitable for oraladministration containing non-hygroscopic carnitine salts with2-aminoethanesulphonic acid, whereas the salts of the inventiondescribed herein are carnitine salts with the chloride salt of2-aminoethanesulphonic acid.

Reading WO98/43945 the expert in the sector would have expected toobtain carnitine salts with the chloride salt of2-amino-ethane-sulphonic acid endowed with a hygroscopicity similar tothat of the salts described in WO98/43945.

The unexpected lower hygroscopicity of the salts according to theinvention described herein, compared with the salts described inWO98/43945, makes them particularly useful for the preparation of solidoral compositions suitable for the above-mentioned purposes.

A further object of the invention described herein is a salt ofL-carnitine with glycine chloride of general formula (II)

where R is hydrogen or a straight or branched lower alkanoyl, with 2-5carbon atoms. The salts in which R is selected from the group consistingof acetyl, propionyl, butyryl, valeryl and isovaleryl are to bepreferred.

Taurine is one of the most abundant amino acids in the body and is to befound in the central nervous system and in skeletal muscle and ismoreover concentrated in the brain and heart. It has been known for sometime now to be an essential nutrient during the growth and developmentof mammals; in fact, it is present in mother's milk and is especiallyimportant for the development of the cerebellum and retina. Taurine alsohas a very important metabolic function: in bile, the bile acids arebound to taurine to form the glycocholic and taurocholic acids,respectively.

The salts of bile acids possess the important property of lowering thesurface tension of solutions. For this reason they are excellentemulsifying agents and perform an important function in the absorptionand digestion of lipids in the bowel.

These important metabolic and nutritional characteristics mean thattaurine when bound to L-carnitine performs a complementary function tothat performed by L-carnitine. In fact, by favouring the emulsificationand digestion of fatty acids, taurine is complementary to the subsequentmetabolic activity exerted by L-carnitine, i.e. the oxidation of fattyacids for energy production.

Glycine is an important amino acid widely used as a food supplement bothin human nutrition and in the feeding of livestock and pets. Thus, thenon-hygroscopic salt of carnitine with glycine also presents an enhancedtherapeutic and/or nutritional value compared to the corresponding innersalt, in that, as already mentioned, the anionic part (glycine)contributes to the therapeutic and/or nutritional value which istherefore no longer determined exclusively by the “carnitine” part ofthe salt.

The non-hygroscopic salts according to the invention described hereinare useful agents in human or animal nutrition both in physiologicalconditions, i.e. in subjects in a good state of health, and in themalabsorption syndromes observed in children and adults.

The salts of L-carnitine and the lower alkanoyl L-carnitines accordingto the invention described herein are non-hygroscopic, are easy toprocess and are highly stable on storage.

Given here below are same examples for the preparation of thenon-hygroscopic salts according to the invention.

EXAMPLE 1 Procedure for the Preparation of Acetyl L-Carnitine Salt withTaurine Chloride (ST 1805)

2.5 g of taurine [0.02 mol] and 4.78 g of acetyl L-carnitine chloride[0.02 mol] were dissolved in the minimal amount of water and vacuumconcentrated at 40° C. The residue thus obtained was extracted withacetone and held overnight under stirring and then filtered and dried.

7.1 g of a non-hygroscopic white crystalline solid were obtained.

Yield: 76%.

DSC=186° C. by decomposition.

NMR in solid phase ¹³C

ppm 67.0 (CH—O); 63.6 (N⁺—CH ₂—CH), 54.1 ((CH₃)₃N⁺); 46.6 (N⁺ CH ₂—CH₂);36.4 (CH ₂CO, CH₂S); 21.9 (CH₃)

NMR: D₂O Hδ 5.6-5.5 (1H, m, —CH—); 3.8-3.6 (2H, m, N—CH ₂); 3.4-3.3 (2H,t, H₂N—CH ₂); 3.2-3.1 (2H, t, CH ₂—SO₃—); 3 (9H, s, (CH₃)₃—N); 2.8-2.7(2H, d, CH ₂—COOH); 2 (3H, s, COCH ₃)

EXAMPLE 2 Procedure for the Preparation of Propionyl L-Carnitine Saltwith Taurine Chloride (ST 1806)

2.5 g of taurine [0.02 mol] and 5.1 g of propionyl L-carnitine chloride[0.02 mol] were dissolved in the minimal amount of water and vacuumconcentrated at 40° C. The residue thus obtained was extracted withacetone, held overnight under stirring, filtered and dried.

7.2 g of a non-hygroscopic white crystalline solid were obtained.

Yield: 98%.

DSC 175° C. by decomposition.

NMR in solid phase ¹³C

ppm 69.5 (CH—O); 66.4 (N⁺—CH ₂—CH), 53.9 ((CH₃)₃); 46.5 (N⁺ CH ₂—CH₂);36.1 (CH ₂CO, CH₂S); 29.6 (OCOCH ₂); 10.4 (CH₃)

NMR: D₂O Hδ 5.6-5.5 (1H, m, —CH—); 3.8-3.6 (2H, m, N—CH ₂); 3.4-3.3 (2H,t, H₂N—CH ₂); 3.2-3.1 (2H, t, CH ₂—SO₃—); 3.1 (9H, S, (CH₃)₃—N); 2.7-2.6(2H, m, CH ₂—COOH); 2.4-2.3 (2H, q, CH ₂CH₃); 1-0.9 (3H, t, CH₂—CH₃ )

EXAMPLE 3 Procedure for the Preparation of Acetyl L-Carnitine Salt withGlycine Chloride ST 1803

2.2 g of glycine hydrochloride (hygroscopic product) [0.02 mol] and 4.06g of acetyl L-carnitine inner salt (hygroscopic product) [0.02 mol] weredissolved in 50 ml of water and vacuum concentrated.

The residue was extracted with acetone and held overnight under stirringand filtered.

The filtrate was vacuum dried at 30° C.

6.1 g of glycine hydrochloride acetyl L-carnitine salt were obtained inthe form of a non-hygroscopic white crystalline solid.

Yield: 95%.

DSC=177° C. by decomposition

NMR in solid phase ¹³C

ppm 67.0 (CH—O); 63.8 (N⁺—CH ₂), 54.5 ((CH₃)₃N⁺); 42.6 (N—CH ₂—CO); 36.3(CH ₂CO); 27.1 (CH₃)

NMR: D₂O Hδ 5.6-5.5 (1H, m, —CH—); 3.7-3.5 (2H, m, N—CH ₂); 3.5 (2H, s,H₂N—CH ₂); 3.1 (9H, s, (CH₃)₃—N); 2.6-2.4 (2H, m, CH ₂—COOH); 2 (3H, s,CO—CH ₃)

EXAMPLE 4 Procedure for the Preparation of Propionyl L-Carnitine Saltwith Glycine Chloride ST 1804

2.2 g [0.02 mol] of glycine hydrochloride (hygroscopic product) and 4.35g of propionyl L-carnitine inner salt (hygroscopic product) [0.02 mol]were dissolved in the minimal amount of water and vacuum concentrated.The residue thus obtained was extracted with acetone and held overnightunder stirring and then filtered and dried.

6.2 g of a non-hygroscopic white crystalline solid were obtained.

Yield: 94%.

DSC=163° C.

NMR in solid phase ¹³C

ppm 69.5 (CH—O); 66.4 (N⁺—CH₂), 53.8 ((CH₃)₃N⁺); 43.1 (N—CH ₂—CO); 35.1(CH ₂CO); 29.6 (OCOCH ₂); 13.3 (CH₃)

NMR: D₂O Hδ=5.6-5.5 (1H, m, —CH—); 3.7-3.5 (2H, m, N—CH ₂); 3.5 (2H, s,H₂N—CH ₂); 3.1 (9H, s, (CH₃)₃—N—); 2.7-2.6 (2H, m, CH ₂—COOH); 2.4-2.3(2H, q, CH₂—CH₃); 1-0.9 (3H, t, CH₂ CH ₃)

The compounds in the examples mentioned are non-hygroscopic and highlystable.

The invention described herein also covers compositions containing astheir active ingredient at least one of the above-mentionedpharmacologically acceptable non-hygroscopic salts well known to expertsin pharmaceutical and food technology and possibly one or moreadditional active ingredients.

Particularly preferred are compositions in solid form suitable for thepreparation of oral administration forms as tablets, chewable tablets orcapsules containing a salt of L-carnitine or alkanoyl L-carnitine offormula (I) or (II) corresponding to 50-2000, and preferably 100-1000 mgof L-carnitine or alkanoyl L-carnitine expressed as an inner salt.

For example, a composition suitable for the production of tablets is thefollowing:

Non-hygroscopic salt of L-carnitine according to the invention 500 mgStarch  20 mg Talc  10 mg Ca-stearate  1 mg 531 mgA composition suitable for the production of capsules is the following:

Non-hygroscopic salt of L-carnitine according to the invention 500 mgLactose  50 mg Starch  20 mg Talc  5 mg Ca-stearate  2 mg 577 mg

1. A solid, stable, non-hygroscopic salt of L-carnitine or alkanoylL-carnitine with taurine chloride of formula (I):

where R is hydrogen or a straight or branched lower alkanoyl with 2-5carbon atoms.
 2. The salt according to claim 1, where R is selected fromthe group consisting of acetyl, propionyl, butyryl, valeryl orisovaleryl.